Hemostasis
The process of blood clotting and The process of blood clotting and then the subsequent dissolution then the subsequent dissolution of the clot, following repair of the of the clot, following repair of the
injured tissue, is termed injured tissue, is termed hemostasishemostasis. .
Haemostasis overview:
BV Injury
PlateletPlateletAggregation
PlateletActivation
Blood VesselBlood Vessel Constriction
CoagulationCoagulation Cascade
Stable Hemostatic Plug
Fibrin formation
Reduced
Blood flow
Contact/ Tissue Factor
Primary hemostatic plug
Neural
Hemostasis - major events 1. Vascular constriction.
2. Platelets become activated by thrombin and aggregate at the site of injury, forming a temporary, loose platelet plug.
3. To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug.
4. The clot must be dissolved in order for normal blood flow to resume following tissue repair.
HK = high molecular
wt. kininogen.
PK = prekallikrein.
PL = phospholipid.
Endogeneous anticoagulants
• AT lll – (binds to thrombin and prevents fibrinogen-fibrin)
• Heparin co-factor II – (homologous with AT lll)
• Prot C – (inhibits activity of factors V and Vll)
• Prot S – (enhances the effect of protein C).
• TFPI – (tissue factor pathway inhibitor - inhibits the
tissue factor-Vlla complex)
Vitamin K Dependent Factors
• Factors II, VII, lX, X.
• Protein C and Protein S
Role of the liver
Loss of liver parenchyma decreases:– all coagulation factors - except F Vlll and von
Willebrand co-factor .– physiologic inhibtors of the coagulation (AT lll,
Prot C and Prot S)– components of the fibrinolytic system ( mainly
plasminogen, and a2 anti plasmines).
• Liver dysfunction induces:– platelet dysfunction– dysfibrinogenemia– accelerated fibrinolysis (impaired clearance of
tissue plasminogen activators t-PA)
Disorders of HemostasisDisorders of Hemostasis
Hematologic disorders causing bleedingHematologic disorders causing bleeding
• Vascular disorders– Scurvy, easy bruising,
• Platelet disorders– Low Number or abnormal
function
• Coagulation disorders– Factor deficiency.
• Mixed/Consumption – DIC
Approach to Bleeding Approach to Bleeding DisordersDisorders
HISTORY• Is the patient bleeding?• Surrogate markers of bleeding
– declining hemoglobin
• Age of onset• Surgical procedures• Medications
– Aspirin, anticoagulants, etc.
• Birth & Family
Approach to Bleeding DisordersApproach to Bleeding Disorders
•Petechiae,
• Echymoses,
• Menorrhagia
• GI bleeding
• Echymoses
• Late wounds bleeding
• Extensive hemorrhage
( joint spaces,
after immu.)
•
• Bleeding from
multiple sites in an
ill patient
Platelet Disorder
Coagulation Disorders
D.I.C.
Approach to Bleeding DisordersApproach to Bleeding Disorders
If a patient has
tolerated tonsillectomy
and / or adenoidectomy
or extraction of multiple wisdom teeth
without major hemorrhage,
a significant
bleeding disorder
is unlikely.
Clinical aspects of bleedingClinical aspects of bleeding
• Do not blanch with pressure (cf. angiomas)
• Not palpable (cf. vasculitis)
Petechiae - (typical of platelet disorders)Petechiae - (typical of platelet disorders)
Platelet Coagulation
Petechiae, Purpura Hematoma, Joint bl.
Clinical aspects of bleedingPlatelet factor disorders Coagulation disorders
Site of bleeding Skin, Mucous membranes (epistaxis, gum, vaginal, GIT)
Deep in soft tissues
Petechiae Yes No
Ecchymoses (“bruises”)
Small, superficial Large, deep
Hemarthrosis / muscle bleeding
Extremely rare Common
Bleeding after cuts & scratches
Yes No
Bleeding after surgery or trauma
Immediate, usually mild Delayed (1-2 days), often severe
Mucus membrane bleeds
Spontaneous With trauma
InvestigationsInvestigations
Platelet countPlatelet count 150,000 to 450,000 platelets per ml of blood. 150,000 to 450,000 platelets per ml of blood. < 20,000 per mL - spontaneous bleeding< 20,000 per mL - spontaneous bleeding
Bleeding timeBleeding time Test for platelet function Test for platelet function in
Normal : 2 - 5 minutes
Prothrombin Prothrombin TimeTime
measures the clotting activity of factors I, II, V, measures the clotting activity of factors I, II, V,
VII, and X VII, and X Normal : 12-15 seconds
Activated Partial Activated Partial
Thromboplastin Thromboplastin
TimeTime
Measures clotting activity of factors I, II, V, VIII, Measures clotting activity of factors I, II, V, VIII,
IX, X, XI, and XII IX, X, XI, and XII Normal : 25 - 39 sec
Factor assays Factor assays Measure the amount of specific clotting factorsMeasure the amount of specific clotting factors
FDPsFDPs Fibrin degradation productsFibrin degradation products
Activated partial thromboplastin time (aPTT
or APTT)
• is a performance indicator measuring the efficacy of both the "intrinsic" (now referred to as the contact activation pathway) and the common coagulation pathways.
• It is also used to monitor the treatment effects with heparin, a major anticoagulant.
aPTT - Interpretation
• Normal = 25 to 39 sec • Prolonged APTT may indicate:
• heparin, • direct thrombin inhibitors, • a deficiency or inhibitor for factors in the intrinsic and
common pathway • factors II, V, VIII, IX, X, XI, XII,
• lupus anticoagulant, • vitamin K deficiency, or • severe liver disease
Whole blood clotting time• 5 ml of blood is placed in a glass container,
kept at body temperature and observed • A clot should occur in 5 to 15 minutes
• Prolonged = Severe deficiency of any of the coagulation proteins
• The clot should retract in 30 to 60 minutes • Weak friable clot = hypofibrinogenaemia • Early dissolution = enhanced fibrinolysis
(Inaccurate)(Inaccurate)
Prothrombin time
• The time taken for plasma to clot after addition of
tissue factor (obtained from animals) and calcium
to citrated blood.
• This measures the quality of the extrinsic pathway
(as well as the common pathway) of coagulation.
Prothrombin time • The reference range for prothrombin time is
usually around 12-15 seconds; • Prolonged
• Deficiencies of factors II, V, VII, X or fibrinogen;
• Liver disease; • Vitamin K deficiency and • Oral anticoagulants (warfarin)
International normalized ratio
• Each manufacturer gives an ISI (International Sensitivity Index) for any tissue factor they make. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 1.4
• The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the control sample used.
Thrombin time• Time to clot formation after the addition of
thrombin to citrated blood • Prolonged by
• Heparin, • Direct thrombin inhibitors, • Fibrin degradation products (FDPs), • Paraproteins, and • Fibrinogen deficiency (both qualitative and
quantitative)
Bleeding time - Ivy method
• A blood pressure cuff is placed on the upper arm and inflated to 40 mm Hg. A lancet is used to make a stab wound on the underside of the forearm.
• The time from when the stab wound is made until all bleeding has stopped is measured and is called the bleeding time.
• Every 30 seconds, filter paper or a paper towel is used to draw off the blood.
• Normal values fall between 2 - 5 minutes depending on the method used
FDPs
• Fragments resulting from the action of plasmin on fibrin or fibrinogen
• Reflect high fibrinolysis states (such as DIC) when they are elevated
Platelet Count
• In an adult, a normal count is about 150,000 to 450,000 platelets / L of blood.
• Platelet levels fall below 20,000/L, spontaneous bleeding may occur and is considered a life-threatening risk.
• Increased platelet counts (thrombocytosis) • Myeloproliferative disorder
Others Tests
• Von Willebrand factor antigen (vWF:Ag): immunoassay for circulating vWF.
• Von Willebrand factor activity (vWF:RCo): measures the functional ability of a patient's vWF to agglutinate platelets in the presence of Ristocetin.
• Factor VIII C activity: is functional assay for factor VIII. It is measured by mixing normal plasma with factor VIII-deficient plasma
• Platelet function studies• Bone marrow examination – plt
Laboratory Evaluation of the Coagulation Pathways
Partial thromboplastin time(PTT)
Prothrombin time(PT)
Intrinsic pathway Extrinsic pathway
Common pathwayThrombin time
Fibrin clot
Thromboplastin Tissue factor Phospholipid
Calcium
Thromboplastin Tissue factor Phospholipid
Calcium
Surface activating agent (Ellagic acid, kaolin)
PhospholipidCalcium
Surface activating agent (Ellagic acid, kaolin)
PhospholipidCalcium
ThrombinThrombin
XII
XI
IX
VIII
XII
XI
IX
VIII
VII
*
*
*
VII
*
*
*
X
V
II
X
V
II
Intrinsic PathwayIntrinsic Pathway Extrinsic PathwayExtrinsic Pathway
- - - - - - - - - - I - - - - - XIII - - - - - - - - - - I - - - - - XIII
Prolonged PTT
ProlongedPT
Both PTT & PT Abnormal or DICor DIC
Urea Stability
Test
Urea Stability
Test
Abnormal PTT, PT &
TT
Abnormal PTT, PT &
TT
Correction Tests
Only PTT abnormal : XI, IX & VIII
(XII never presents clinically)
Abnormal PTT corrected by
Plasma Adsorbed Serum
VIII Yes No
IX No Yes
Some Rules of Thumb
Both aPTT and PT Elevated
Only PT prolonged
Only aPTT prolonged
von Willebrand Disease
An inherited bleeding disorder described by Finnish Physician
Erik Adolf von Willebrand
Low levels of a protein called von Willebrand factor that helps the blood to clot
Von Willebrand factor that doesn’t work properly
Platelet Activation and von Willebrand Factor (vWF)
In order for hemostasis to occur, platelets must adhere to exposed collagen, release the contents of their granules, and aggregate.
The adhesion of platelets to the collagen exposed on endothelial cell surfaces is mediated by von Willebrand factor (vWF).
The function of vWF is to act as a bridge between a specific glycoprotein on the surface of platelets (GPIb/IX) and collagen fibrils.
vWF binds to and stabilizes coagulation factor VIII.
Binding of factor VIII by vWF is required for normal survival of factor VIII in the circulation.
Platelet Activation and von Willebrand Factor (vWF)
Type 1Low level of von Willebrand factor. The level of
factor VIII may also be lower than normalMildest and most common form of the disease. About 3 out of 4 people diagnosed with vWD have
type 1 disease.
Type 2Defect in von Willebrand factor causes it to not
work properly. Type 2 is divided into 2A, 2B, 2M, and 2N. Each is treated differently, so knowing the exact type is important.
Type 3No von Willebrand factor and very low factor VIII. Type 3 is severe and very rare.
von Willebrand Disease
von Willebrand Disease
Incidenceroughly about 1 in 100 individuals.
Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation.
It may be more severe or apparent in people with blood type O.
Genetics vWF gene is located on chromosome twelve (12p13.2).
o Types 1 and 2 are inherited as autosomal dominant traits and
o type 3 is inherited as autosomal recessive.
o Occasionally type 2 also inherits recessively.
von Willebrand Disease
von Willebrand Disease
Weibel-Palade bodies Organelles in the endothelial
cells There are two major
constituents
1. von Willebrand factor (vWF), a multimeric protein involved in blood coagulation
2. The second is P-selectin - binds to passing immune cells (leukocytes).
Manifestations:Bruising that's unusual in location or frequency
Abnormal menstrual bleeding Bleeding in the mucous membranesExcessive or prolonged bleeding after a tooth extraction or tonsillectomy
von Willebrand Disease
Bleeding time
Factor VIII level test (factor VIII coagulant)
von Willebrand factor antigen test (factor VIII antigen) - which measures the amount of von Willebrand factor. ( mild if a person has 20% to 40% of the normal, severe if the amount is less than 10% of normal. )
Ristocetin co-factor activity test measures how well the von Willebrand factor is working
von Willebrand factor multimers test - to classify the type of vWD
Platelet function tests which determine how well the platelets work and help identify the type of vWD or
the presence of another disorder
Tests may need to be done more than once because these levels may rise and fall over time in an individual.
Investigations
Treatment: No regular treatment Prophylactic treatment is sometimes
given for patients are scheduled for surgery.
They can be treated with human derived medium purity factor VIII concentrates complexed to vWF
Mild cases - treated with desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP)
Rises patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells
von Willebrand Disease
- CSN Vittal- CSN Vittal
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